Comment

Contrary to the implication in some obituaries, Max Perutz, who died on February 6
2002 in Cambridge, England, just a few months before his 88th birthday, did not determine
the first three-dimensional structure of a protein molecule. John Kendrew did that.
Max did determine the structure of the hemoglobin molecule (Figure 1), but Kendrew's low-resolution myoglobin structure predated the 5.5 Ångstrom-resolution
hemoglobin structure by more than a year, and when Max published his low-resolution
work showing that hemoglobin had the same all-helical fold as myoglobin, Kendrew was
publishing his interpretation of myoglobin at 2 Ångstroms resolution, in full atomic
detail.

Nor, as many people have assumed, did Max invent the method used to determine those
two structures, and thousands that have come after them. The method was invented years
earlier for small organic molecules by J. M. Robertson of Glasgow University, in a
series of brilliant crystallographic studies. Robertson had even suggested at the
time that the so-called isomorphous replacement method might be used to solve the
structures of very small proteins like insulin. But no one believed it could work
for a protein the size of myoglobin, much less hemoglobin, which is four times larger
- no one except Max Perutz.

Against the prevailing opinion of nearly every physicist, Max did the experiment.
He did it because he had realized that, while the scattering from the thousands of
atoms in a protein crystal was weak because the structure was spread out over a large
volume, the scattering from a single heavy atom such as mercury, bound to the protein
in a specific place, would be strong enough to produce measurable changes in the intensities
of the protein X-ray reflections. When Max Perutz showed that these changes not only
could be measured reproducibly but also could be interpreted to determine the so-called
phases of the protein reflections in the same way Robertson had done, Kendrew was
able to use the method to solve myoglobin. It was as much for that pioneering development
of the method as it was for the hemoglobin structure that Max Perutz shared the Nobel
Prize in Chemistry in 1962 with John Kendrew, who by the way had been Max's first
doctoral student many years before.

Since then, anyone who has determined a protein structure by X-ray crystallography
has followed in Max's footsteps, but his legacy is much larger than that. I don't
even intend to mention his founding of the famous Laboratory for Molecular Biology
in Cambridge, which has been home to ten Nobel Prize winners since the late 1950s.
For me, his greatness - and his relevance to all of us in the age of genomics - rests
on two other pillars. "I wanted to solve an important problem in biology," Max once
said when asked what had motivated him to undertake to solve the structure of hemoglobin
when most people believed that it was impossible to determine the exact position in
space of all of the atoms in anything so large as a protein molecule. He wasn't referring
to doing the first protein crystal structure either. The problem Max wanted to solve
was a problem in biology, not physics. He wanted to figure out how hemoglobin works.
Everything he did, including working out the method to crack the phase problem in
protein crystallography, was a means to that end.

Max needed to see what hemoglobin looked like because he knew it was impossible to
understand how it functions without that information. For him, structure was always
in the service of the biological question. Nothing proves that more than the fact
that, once the structure was solved, he didn't do what most other crystallographers
have done since: go on to the next new protein structure. He kept working on hemoglobin.
He kept working on it because that first structure alone didn't answer all of the
biological questions. So Max studied mutant hemoglobins with abnormal oxygenation
properties from people with genetic diseases, and he worked on hemoglobins from animals
with unusual physiology, and he looked that the protein at different pH values and
with allosteric regulators bound, and so on, until the very last years of his life.
It was only in the past few years that he began work on another problem, that of the
structural and functional consequences of repeating sequences such as those found
in the protein involved in Huntington's disease. He had just sent off a set of papers
on this subject before he died, and as always, his structural studies were driven
by the underlying biological problem. In an era when data-gathering for its own sake
is much in vogue, including the gathering of reams of protein structure data, Max's
scientific life reminds us that the best science is usually driven by a passion to
find the answer to a fundamental and important question.

The other great thing Max did was to embark, in his 70s, on a second career: as a
writer of popular essays on science and scientists. Over the past two decades he penned
numerous articles in places like The New Yorker and The New York Review of Books and the Times Literary Supplement. Some of the best of the early ones have been collected in the book Is Science Necessary?: Essays on Science and Scientists, published in 1991 by Oxford University Press. Not a sparingly elegant stylist - he
never met a polysyllabic word he didn't like, and his sentence structure tended towards
the convoluted - his writing nonetheless passes the supreme test of being not only
readable but rereadable. Not bad for someone who, like Conrad, was not a native-born
English speaker. My favorite of Max's pieces is Enemy Alien, a delightful account of his internment in Canada in the early months of World War
II (because of his Austrian origin), followed by his service in a bizarre undertaking
to build giant warships out of icebergs. In these writings he not only defends, brilliantly,
the importance of science and scientists, he also puts a human face on what we do,
and explains it so that the lay public can be both enlightened and entertained.

The great Soviet neuropsychologist A.R. Luria believed that scientists are obliged
to produce two kinds of writings: the dry technical reports of their work, and stories
told for everyone to understand. He did both wonderfully (if you don't know his work,
I recommend The Man With a Shattered World (New York: Basic Books; 1972), his moving account of a soldier with a terrible brain
wound), and established a tradition that has been carried on magnificently by Oliver
Sacks, whose latest book, Uncle Tungsten (New York: Alfred A. Knopf; 2001), is as good as his classic The Man Who Mistook His Wife for a Hat (London: Gerald Duckworth; 1985). It is hard to think of anything more important
than helping the public - who after all put us in the laboratory and trust us to work
for their ultimate benefit - to develop a sense of familiarity with what we do and
an understanding of what it might mean for them. Genomics is rapidly producing all
sorts of discoveries that make lay people profoundly - and perhaps justifiably - uneasy.
Max showed us that our obligation does not end with our best efforts in the laboratory.
We can't all write the way he did, but we can all find ways to reach out to nonscientists
with the same affection, clarity, and lack of condescension.

Max Perutz had two children who bore his name, but his work and his ideas produced
thousands of progeny. No other form of scientific immortality seems to me more worthwhile.